mini-review transthyretin amyloidosis and the kidney...amyloidosis. most hereditary amyloidoses are...

Mini-Review

Transthyretin Amyloidosis and the Kidney

Luısa Lobato*†‡ and Ana Rocha*

SummaryThe amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulinlight chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis(ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associatedwith at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine forvaline at position 30 is the most common mutation. Each variant has a different organ involvement, althoughclinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheralneuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairmentand proteinuria are also clinical features. This review combines clinical and laboratory findings of renalinvolvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteennephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathyaffects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Micro-albuminuria can be the disorder’s first presentation, even before the onset of neuropathy. Amyloid renal depositscommonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy isbased on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, livertransplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is rec-ommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in developmentmay soon be available.

Clin J Am Soc Nephrol 7: 1337–1346, 2012. doi: 10.2215/CJN.08720811

IntroductionAmyloidosis is caused by extracellular deposition ofmisfolded proteins as insoluble amyloid fibrils thatprogressively disrupt tissue structure and function.

The most common forms of systemic amyloidosisare associated with plasma cell dyscrasias (AL andAH amyloidosis), chronic inflammation (AA amyloid-osis), dialysis (b2-microglobulin amyloidosis), age (senilesystemic amyloidosis), and inherited gene mutations.Proteins that cause familial forms of amyloidosis aretransthyretin (TTR), apolipoprotein-AI, apolipoprotein-AII, gelsolin, fibrinogen Aa-chain, lysozyme, and cys-tatin C. All except the cystatin C clinically affect thekidney. The recently described leukocyte chemotacticfactor 2 (LECT2), which has no evident familial trait,is also included in the nephropathic forms of systemicamyloidosis.

Most hereditary amyloidoses are due to TTR muta-tions. Although kidney deposits were recognized in theoriginal description of the disease (1), a renal phenotypeof TTR amyloidosis (ATTR) has been overlooked. Thisreview discusses the effects of ATTR on the kidney, withspecial attention to the most common mutation, V30M(c.148G.A, p.Val50Met, applying the new nomencla-ture of the Human Genome Variation Society). The in-troduction of new therapies will also be reviewed.

TransthyretinTTR is one of most abundant circulating proteins

belonging to a subset of 25 proteinswith a predisposition

to misfold. It is synthesized by the liver (90%), retina,pancreas, and choroid plexus as a 55-kD tetramer withfour identical 127-residue b-sheet–rich subunits and a20-residue signal peptide with no specific physiologicproperties (2,3). TTR mRNA has been found in kidneycells (4). TTR binds to thyroxine and retinol-bindingprotein in the blood and cerebrospinal fluid and trans-ports vitamin A without the loss of retinol-binding pro-tein molecules in the kidney (5).The TTR gene is located on human chromosome 18

(18q11.2-q12.1) (6), and more than 100 different single-or double-point mutations and a deletion are described.Pathogenic mutations are associated with the fibrillarconformation of proteins and, subsequently, amy-loidosis. Amino acid substitutions result in confor-mational changes in the protein that lead to weakersubunit interactions between the tetramers. The dis-sociation into monomers is the first step in the devel-opment of amyloidosis. Modified soluble tetramersexposing cryptic epitopes appear to circulate in pa-tients, but the trigger leading to dissociation into mo-nomeric and oligomeric intermediates is not completelyunderstood.Fibrillar deposits are formed only in mid- to late

adulthood. This could be because the mechanisms thatpromote amyloidogenesis become more active withaging or the preventive factors become less effectivewith increasing age. Nonmutated TTR also formsdeposits, suggesting that mutations are not the soledetermining factor in amyloid fibril formation and that

*Department ofNephrology and†Unidade Clınicade Paramiloidose,Hospital de SantoAntonio, CentroHospitalar do Porto,Porto, Portugal;and ‡UnidadeMultidisciplinarde InvestigacaoBiomedica, ICBAS-Instituto de CienciasBiomedicas AbelSalazar, Universidadedo Porto, Porto,Portugal

Correspondence:Dr. Luısa Lobato,Department ofNephrology, Hospitalde Santo Antonio,Centro Hospitalar doPorto Largo Prof. AbelSalazar, 4099-001Porto, Portugal. Email:[email protected]

www.cjasn.org Vol 7 August, 2012 Copyright © 2012 by the American Society of Nephrology 1337

mailto:[email protected]

wild-type (WT) TTR has an intrinsic amyloidogenic pro-perty (7).Deposition of WT-TTR results in senile systemic amyloid-

osis (SSA), whereas its variants or fragments are associatedwith forms that are transmitted in an autosomal-dominantmanner. Some nonpathogenic gene mutations appeared toprovide a protective effect with a slower disease progression(8). Because the liver is the main source of circulating TTR,orthotopic liver transplantation (OLT) was proposed fortreatment of ATTR (9).

Epidemiology and GeneticsATTR is the most common form of hereditary amyloid-

osis. This disease was described by Andrade in Portugal (1)and was later reported in Sweden (10) and Japan (11). Theinitial reports of ATTR emphasized peripheral neuropa-thy, leading to the term familial amyloidotic polyneuropathy(FAP); that condition affects 1/100,000 people, althoughthis number varies by country (12). In an endemic areaof Portugal, the prevalence of ATTR V30M is 1/1000,which is similar to its prevalence in Sweden (13,14). Themutations with predominant heart manifestations includethe ATTR I111M and the ATTR V122I, which are presentin 3.5% of the African-American population (15). Althoughthe TTR mutation is required for amyloidosis, carriers ofthe same mutation present variable penetrance. This char-acteristic suggests that genetic modifiers, epigenetic factors(16), or environmental influence exist. Several candidategenes have been hypothesized but none have been identified(17). On the basis of the finding that penetrance is higherwhen the disease is maternally inherited, it was recentlysuggested that a mitochondrial polymorphism might par-tially explain differences in penetrance (18). Studies on theinfluence of environmental factors in kidney amyloidosis arecontradictory. Renal deposits in transgenic mice expressingthe human TTR gene were absent in specific pathogen-freeconditions (19) but persisted in other experimental evalua-tions under the same environment (20).There is a slight male predominance of ATTR V30M,

except in nonendemic areas of Japan where women arerarely affected (21). Epidemiologic differences, shown inTable 1, have a special importance in nephropathy (22).

Clinical PresentationEthnicity and the TTR variant affect organ involvement,

although differences exist between patients with the samemutation and within the same family (Table 2).The principal manifestation of most ATTR amyloidosis is

peripheral neuropathy with dysautonomia. In the era beforeOLT, patients died on average 11 years after disease onset(23). The age of onset ranges from 17 to 80 years (12). InPortugal and Japan, disease caused by the ATTR V30M var-iant usually develops between the third and fourth decadesof life. Complement factor C1Q polymorphisms may mod-ulate the age of onset and explain genetic anticipation withamyloid deposition at an earlier age in successive genera-tions (24). In monozygotic twins from Spain, different agesof onset and phenotypes, including dissimilar kidney in-volvement, have been reported (25). Of note, homozygositywas not described as conferring a worse prognosis of ne-phropathy in Swedish (26) and Japanese (27) populations.

Non-neurologic features include involvement of the heart,eye, gastrointestinal tract, and kidney. A small number ofATTR V30M cases, especially late-onset cases, may presentwith heart failure (28). Precocious anemia, unrelated torenal manifestations, is conferred by low erythropoietinlevels (29,30). It was suggested that the distal nephron isthe major site of erythropoietin production in ATTR (31).

Renal ManifestationsMuch of the literature on renal involvement in ATTR is

based on small series. The assessment of different muta-tions is not homogeneous; some reports specify the clinicalmanifestations, and others simply describe the presence ofrenal amyloid deposits. The distribution of amyloidwithin organs can be demonstrated using 123I conjugatedwith serum amyloid P component, a glycoprotein presentin all amyloid deposits (32). Although scintigraphy with123I serum amyloid P component can depict extensive amy-loid deposits in organs in which they have not been suspec-ted clinically, there is a poor correlation with the severity oforgan dysfunction. In addition, this modality is unavailablein most centers (33).The first study dedicated to renal involvement in ATTR

V30M was conducted in Sweden (10). Serum creatininewas increased in 5 of the 26 patients examined, and uremiacontributed to death in 4 of them. Another study fromSweden, which included 24 patients, showed that halfhad renal insufficiency and proteinuria (34). Nephropathydid not correlate with age, duration of disease, or severityof neuropathy. In Japan, early manifestation of heavy pro-teinuria was also identified (35). A Portuguese prospectivestudy (36) involving 22 asymptomatic TTR V30M genecarriers and 32 patients with neuropathy showed that mi-croalbuminuria appears within the third and fifth years ofdisease and can precede the onset of neuropathy. Aftermicroalbuminuria, overt nephropathy developed in halfof the patients, usually 2 years later. Renal failure gener-ally occurred 5 years after microalbuminuria, and evensooner in women. The average duration of neuropathy at

Table 1. Characteristics of transthyretin-associatedamyloidosis V30M with nephropathy

Epidemiology andGenetics Findings

Origin Nonendemic areasFamily history Frequently absentGender predominance FemaleAge of onset ofneuropathy

.40 yr confers 3.5-foldincreased risk fornephropathy

Clinical anticipationwithin the family

Frequently present

Familial aggregation ofnephropathy

Present especially insiblings of ESRDprobands

Source: Lobato L, Beirão I, SilvaM et al: End-stage renal diseaseand dialysis in hereditary amyloidosis TTR V30M: presentation,survival and prognostic factors. Amyloid 11: 27–37, 2004.

1338 Clinical Journal of the American Society of Nephrology

first dialysis was 10 years. In the pre-OLT era, a serialstudy involving 403 Portuguese patients from 150 kin-dreds showed that one third of the patients presented pro-teinuria and 10% progressed to ESRD (22,37). Proximaltubular syndromes were never assigned to ATTR V30M.The ATTR variants with renal involvement are detailed

in Table 2. Proteinuria was not reported in SSA (WT-TTR)or TTR-associated cardiomyopathy.

Renal PathologyIn transgenic mice, WT and variant TTR are present in

the kidney in fibrillar and nonfibrillar aggregates (38). InFAP, the deposition of TTR in cell culture in the form ofsmall toxic nonfibrillar aggregates may occur before amy-loid formation (39), suggesting that prefibrillar oligomerscan cause cell death. Mice with multiple copies of the WThuman TTR gene showed nonfibrillar, noncongophilic anti-human TTR-positive deposits in a smooth pattern along theglomerular and tubular basement membranes. Older ani-mals developed dense congophilic amyloid deposits in theglomeruli and focal deposits in the interstitium. Of note, inelderly Swedish patients with SSA (WT-TTR), postmortemanalysis revealed minimal congophilic material in the renal

cortex, although, as previously mentioned, SSA is not asso-ciated with proteinuria (40). Some authors associate weakCongo red staining of the fibrils with delayed disease onsetand associate a strong affinity to Congo red with early pre-sentation of the disease (41). In the kidney, staining charac-teristics of amyloid deposits were not described as beingdifferent in cases of early- and late-onset neuropathy.A crucial matter in ATTR nephropathy is recognizing the

presence and distribution of renal amyloid deposits. Fourstudies systematically evaluated the renal histopathologyin ATTR V30M. Of those, three were concerned with 14patients of Portuguese origin each and the other with 13Japanese cases.In one report, in which half the patients studied had

normoalbuminuria, amyloid was found in all cases (42). Inanother report, which involved only 4 patients with pro-teinuria, 13 of the 14 patients had amyloid deposits (36). Athird study demonstrated the presence of deposits in all pa-tients, even in the 9 in whom proteinuria was absent (43).Finally, in the Japanese cohort, there was evidence of amyloidin 12 cases; proteinuria was verified in 5 of these cases (44).Patients with albuminuria had a more extensive amyloid

involvement than those without clinical renal disease. Themedulla, basement membrane of distal tubules, loops of

Table 2. TTR variants with kidney involvement

TTR VariantDNA

NucleotideNomenclature

Phenotype Kidney Geographic Focus Reference

Val30Met (p.Val50Met) c.148G.A PN, AN, eye,kidney

Proteinuria,CRF, amyloiddeposits,123I-SAP

Portugal, Japan,Sweden,USA, Mallorca,Cyprus

63

Val30Ala (p.Val50Ala) c.149T.C Heart, AN, PN,kidney

Amyloiddeposits

USA, Germany,China

64

Phe33Cys (p.Phe53Cys) c.158T.G CTS, heart, eye,kidney

Amyloiddeposits

USA 65

Phe33Ile (p.Phe53Ile) c.157T.A PN, AN, eye,kidney

Amyloiddeposits

Poland 66

Gly47Glu (p.Gly67Glu) c.200G.A Heart, PN, AN,kidney

CRF, amyloiddeposits,123I-SAP

Turkey, USA,Germany

67

Ser52Pro (p.Ser72Pro) c.214T.C PN, AN, heart,kidney

CRF, amyloiddeposits

UK, Portugal 68

Gly53Glu (p.Gly73Glu) c.218G.A Heart, kidney CRF Sweden, Basque 69Ile73Val (p.Ile93Val) c.277A.G PN, AN, kidney CRF Bangladesh 70Ser77Tyr (p.Ser97Tyr) c.290C.A Heart, kidney, PN CRF USA, France,

Germany71

Tyr78Phe (p.Tyr98Phe) c.293A.T PN, CTS, skin,heart

CRF France, Italy 72

His88Arg (p.His108Arg) c.323A.G PN, heart, kidney CRF Sweden 69Glu92Lys (p.Gln112Lys) c.334G.A Heart, kidney Amyloid

depositsJapan 73

Val94Ala (p.Val114Ala) c.341T.C Heart, PN, AN,kidney

Amyloiddeposits

Germany, USA 74

Ser112Ile (p.Ser132Ile) c.395G.T PN, heart, kidney CRF Italy 75Asn124Ser (p.Asn154Ser) c.371A.G Kidney, heart Proteinuria,

amyloiddeposits

Italy 76

PN, peripheral neuropathy; AN, autonomic neuropathy; 123I-SAP, kidney deposits in scintigraphy with 123I-labeled serum amyloidP component; USA, United States of America; CTS, carpal tunnel syndrome; eye, vitreous opacities; CRF, chronic renal failure.

Clin J Am Soc Nephrol 7: 1337–1346, August, 2012 Transthyretin Amyloidosis and the Kidney, Lobato and Rocha 1339

Figure 1. | Light microscopy findings in transthyretin-associated amyloidosis (ATTR) showing that amyloid deposition can be foundin glomeruli, vasculature, and tubulointerstitium. (A) Massive deposits in the glomerulus, ATTR V30M-amyloidosis, antitransthyretin(TTR) fixation (immunoperoxidase technique; original magnification, 3400). (B) Deposits in the arteriole at the vascular pole–sparing me-sangial areas, ATTR V30M-amyloidosis (Congo red; original magnification, 3400). (C) Amyloid in a blood vessel in conjunction with glo-merular deposits, ATTR V30M-amyloidosis (Congo red–stained material under polarized light leads to apple-green birefringence; originalfixation, 3200). (D) Heavy amyloid infiltration of a blood vessel in ATTR V30M-amyloidosis (Congo red–stained material under polarizedlight; original fixation, 3400). (E) Congo red positivity in the medullary interstitium, an early lesion in ATTR V30M-amyloidosis (originalmagnification, 3100). (F) Anti-TTR fixation in the tubular basement membrane, ATTR S52P-amyloidosis (immunoperoxidase technique;original magnification, 31000).


Henle, and interstitium are typically filled with amyloid,even in the early stages of the disease. Proximal tubulespositively react with anti-TTR antibody inside the cells,which can be sustained by internalization of TTR by megalin(45,46).Renal dysfunction and the degree of proteinuria are

correlated with heavy amyloid deposition in the glomeruli,arterioles, and medium vessels, but not with deposition inmedullary tissues (42). Renal deposition does not parallelthat of myelinated nerve fiber loss in the sural nerve, sug-gesting that evolution and severity of nephropathy are notcorrelated with the degree of neuropathy (21,44,47).Amyloid was found predominantly in vessels and tubular

basement membrane in ATTR S52P. Detailed pathologicdescriptions of other variants are not available.The first case of de novoATTR in a renal graft was observed

in an asymptomatic gene carrier for TTR V30M 13 years aftertransplantation (Lobato L, unpublished data). In this case,primary GN led to ESRD. Figure 1 shows patterns of amy-loid deposition in ATTR amyloidosis.

Treatment of ESRDTo date, only one published study has evaluated ATTR

patients undergoing long-term dialysis (48). This reportincluded 62 patients with ATTR V30M who initiated di-alysis at a mean age of 52 years. The main indications fordialysis were fluid overload and metabolic acidosis. Averagesurvival after initiation of hemodialysis was 21 months, withsepticemia being the leading cause of death. Decubitus ul-cers, followed by catheter sepsis and pneumonia, were themajor sources of infections; untreatable hypotension and ca-chexia were additional causes of death. Symptomatic intra-dialytic hypotension was present in more than half of allpatients and predominated in patients with native arterio-venous fistula thrombosis.In patients who did not survive beyond the first year of

dialysis, the absence of a pacemaker represented a two-foldincreased risk for death. This observation is probably relatedto reduced heart rate variability in the face of the combinationof amyloidosis with uremia (49). As previously described,when the use of a pacemaker is advisable in patients withamyloidosis, the general recommendations must be fol-lowed; however, the threshold for implanting these devicesis usually very low, given that other coexisting factors (au-tonomic neuropathy and hypoalbuminemia) exacerbate epi-sodes of low cardiac output (50).Gastrointestinal disturbances, malnutrition, and physical

disability compromise self-peritoneal dialysis care, whichrequires assisted treatment. Peritoneal dialysis in ATTR isprobably a residual treatment, and no sustained experienceis reported.The suitability of isolated kidney transplantation is com-

promised once constant production of the amyloidogenicprecursor protein by the liver is maintained. In contrast toother types of hereditary nephropathic amyloidosis, inATTR this approach was not attempted (51).

Treatment of ATTRCurrently, there is no specific therapy to remove exist-

ing amyloid deposits of any origin. Because the liver is the

organ primarily responsible for the production of circulat-ing precursor amyloidogenic protein in ATTR, OLT is per-formed as a potential curative treatment to eliminate themutant TTR from plasma (52). In the first descriptions ofthis treatment, OLT was used to modify neuropathy pro-gression (53). OLT outcomes are not always favorable, andeven successful treatments are controversial in terms ofnephropathy progression. Scintigraphy with 123I serumamyloid P component showed mobilization of visceral am-yloid, namely in the kidney, although mobilization of re-nal deposits by histology has never been proven (54).Support for de novo amyloid deposition was demonstratedby the type of fibrils extracted from the kidney before OLT(55). The fibrils did not contain obvious WT-TTR; how-ever, after OLT, WT-TTR was evident, in a process similarto that in the heart, although in a less substantial amount.The analysis of fibrils extracted from myocardium tissueafter OLT revealed a greatly increased ratio of WT to var-iant TTR, suggesting that pre-existing amyloid fibrils caninduce the formation of rapidly progressive deposits (56).This unique vulnerability of heart tissue for continued de-position of WT-TTR is not understood (57).During the first year after OLT, renal function significantly

declined in Swedish patients, with stabilization thereafter(58). Portuguese studies demonstrated that proteinuria maybe augmented, occur de novo, or remit. Long-term dialysiswas implemented 7 years after OLT, although a substantialgain in survival was possible (59). In one patient, histologicassessment revealed more extensive deposits and interstitialnephritis.Therefore, in the presence of progressive renal insuffi-

ciency or proteinuria, a kidney biopsy provides informationthat is useful for adjusting immunosuppressive therapy anddetermining whether heavy amyloid deposits are the maincause of ESRD. Japanese researchers recommended renalbiopsy to determine the contraindications for liver trans-plantation (44). In a French study of eight patients whounderwent a second renal biopsy 2 years after transplan-tation, no significant changes in deposits or toxicity due tocalcineurin inhibitors were detected (43).Simultaneous liver-kidney transplantation represents a

therapy for ESRD and avoids recurrence of nephropathy.The Familial World Transplant Registry reports 32 suchtransplantations in patients with ATTR V30M and 1 in apatient with Val94Ala; in addition, a patient with Ser77Tyrunderwent both liver-kidney transplantation and hearttransplantation. In our center, six patients (mean durationof neuropathy, 8 years) had liver-kidney transplantation(60). After 84 months proteinuria had not recurred, but nohistologic evaluation was done.The use of FAP livers as allografts for other patients, also

known as domino transplantation, has raised concernsabout the risk for de novo disease (61). In our center, in-terstitial amyloidosis in the kidney was also demonstrated8 years after a domino procedure (Vizcaíno R, unpublisheddata).New strategies have been developed to treat FAP despite

the scarcity of organs and doubts concerning long-termresults (62). Several trials, some already completed andothers recruiting participants, are evaluating or will eval-uate new drugs (Table 3). A decision tree for ATTR amy-loidosis is presented in Figure 2.


Table 3. Treatment options for transthyretin-associated amyloidosis, classic therapy, and novel agents

Proposed Treatment Action Applicability Reference

Liver transplantation (OLT) Eliminate source of geneticallyvariant protein

Clinical use 9

OLT + kidney transplant Same as for OLT + therapy for ESRD Clinical use 60OLT + kidney transplant +heart transplant

Same as for OLT + therapy forESRD and severe heart failure

Clinical use 77

Diflunisal Binds to TTR via a T4-binding sitestabilizing TTR tetramer

Clinical trial 78250 mg twice day or500 mg once day, oral

Diclofenac, flufenamic acid Same as for diflunisal Preclinical 79In vitro study

Trivalent chromium (Cr3+) Facilitates binding of T4,(presumably) stabilizing TTRtetramer

Preclinical 80Ex vivo human clinical

Fx-1006A (tafamidismeglumine)

Prevents misfolding of the proteinby stabilization of TTR tetramer

Clinical use 8120 mg once day, oral

Cyclodextrin Reduces amyloid deposits bydecreasing conformationalchange of TTR

Preclinical 82In vivo transgenic mousestudy

Doxycycline + TUDCA Removes TTR toxic aggregates anddisrupts TTR fibril

Clinical trial 83Doxycycline, 200 mg onceday, + TUDCA, 750 mgonce day, oral

bis-D-proline compound +anti-SAP antibodies

Disaggregates amyloid depositsthrough binding to high affinity toSAP; triggers its rapid clearance bythe liver and triggers phagocyticclearance mechanisms by potent,complement-dependent,macrophage-derived giant-cellreaction

Pre-clinical 84In vivo transgenic mousestudy

Carvedilol Reduces amyloid deposits mediatedby antioxidant effect


Epigallocatechin-3-gallate Disaggregates amyloid deposits anddecreases nonfibrillar TTRdeposition


Monomers of T119M Exchanges subunits to form highlystable heterotetramers that are lessamyloidogenic

Preclinical 87In vitro study

Single-strandedoligonucleotides

Repairs genes (conversion of TTRgene)


Anti-sense oligonucleotides Suppresses TTR mRNA Levels Preclinical 89In vivo transgenic mousestudy

TTR small interferingRNA (siRNA)

Inhibits TTR expression 90

ALN-TTR01: first-generationlipid nanoparticle

Clinical trial

ALN-TTR02: second-generation lipidnanoparticle

Single endovenous dose

ALN-TTRsc: subcutaneous Clinical trialSingle endovenous dose,.10- fold enhancedpotency comparedwith ALN-TTR01

PreclinicalIn vitro study

OLT, orthotopic liver transplantation; TTR, transthyretin; T4, thyroxine; TUDCA, tauroursodeoxycholic acid; SAP, serum amyloidP component.


Final RemarksIn ATTR, the occurrence and onset of nephropathy vary

according to the mutation. The possibility of old asymp-tomatic gene carriers suggests that ATTR nephropathymay be present, regardless of its absence in family history.It is important to suspect ATTR in patients presenting withproteinuria, progressive renal failure, weight loss, periph-eral neuropathy, and cardiac dysrhythmias.Urinary biomarkers specific for tubular and interstitial

pathologic abnormalities are needed for early detection andtimely treatment. Until now, trials did not clarify whetherkidney disease is an exclusion criterion for a drug or an

option for a particular one. New therapies will highlightimportant issues for nephrologists and groups devoted toamyloidosis.

AcknowledgmentsThe authors thank Professor Idalina Beirão from the Department

of Nephrology of Hospital de Santo António and Dr. Ramón Viz-caíno from the Department of Pathology of Hospital de SantoAntónio, Porto, Portugal, for collaboration. They thank EduardoRothes for manuscript preparation.This work was partially supported by Unidade Multidisciplinar

de Investigação Biomédica, Universidade do Porto.

Figure 2. | Algorithm of diagnosis, treatment of nephropathy, and general recommendations for transthyretin-associated amyloidosis(ATTR). The results of immunohistochemistry for ATTR can be equivocal and difficult to interpret. Recently, mass spectrometry based onproteomic methods has been applied to subtype amyloidosis. SSA, senile systemic amyloidosis; TTR, transthyretin.


DisclosuresNone.

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